1、4.The structure and functions of LysosomesA.Characteristics of Lysosomes Lysosome is a heterogenous organelle:Primary lysosomesSecond lysosomes heterophagic autophagicResidual bodyPrimary Lys.Second Lys表表1.神经鞘脂神经鞘脂贮积病积病疾病缺失酶类主要贮积底物后果GM1神经节苷脂贮积症GM1-半乳糖苷酶神 经 节 苷 脂GM1智力迟钝，肝脏肥大，骨骼受累，2岁前死亡泰萨二氏病己糖胺酶A神 经 节
2、 苷 脂GM2智力迟钝，失明，3岁前死亡法布莱氏病-半乳糖苷酶A三己糖神经酰胺皮疹，肾功能丧失，下肢疼痛山霍夫氏病己糖胺酶A和B神 经 节 苷 脂GM2和红细胞糖苷酯与泰萨氏疾病症状相似，但发展更快高歇氏病葡糖脑苷酯酶葡糖脑苷脂肝脏和脾脏肿大，长骨腐蚀，只在婴儿期发生智力迟钝尼-皮二氏病鞘磷脂水解酶鞘磷脂肝脏和脾脏肿大，智力迟钝Farbers 脂肪肉芽肿病神经酰胺水解酶神经酰胺疼痛性与退行性的关节变形，皮肤瘤，几年内死亡Krabbes 病半乳糖脑苷酯酶半乳糖脑苷脂髓磷脂缺失，智力迟钝，2岁前死亡脑硫脂沉积芳基硫酸酯酶脑硫脂智力迟钝，前十年死亡D.Biogenesis of LysosomesF
3、igure 6-23 The transport of newly synthesized lysosomal hydrolases to lysosomes.The precursors of lysosomal hydrolases are covalently modified by the addition of mannose 6-phosphate in the CGN.They then become segregated from all other types of proteins in the TGN because a specific class of transpo
4、rt vesicles budding from the TGN concentrates mannose 6-phosphate-specific receptors,which bind the modified lysosomal hydrolases.These vesicles subsequently fuse with late endosomes.At the low pH of the late endosome the hydrolases dissociate from the receptors,which are recycled to the Golgi appar
5、atus for further rounds of transport.In late endosomes the phosphate is removed from the mannose on the hydrolases,further ensuring that the hydrolases do not return to the Golgi apparatus with the receptor.Mannose 6-phosphate residues target proteins to lysosomesTargeting of soluble lysosomal enzym
6、es to endosomes and lysosomes by M-6-P tag Phosphorylation of mannose residues on lysosomal enzymes catalyzed by two enzymesRecognition site binds to Signal patchGlcNAc phosphotransferasephosphodiesteraseFigure 6-40.The mannose 6-phosphate(M6P)pathway,the major route for targeting lysosomal enzymes
7、to lysosomes.Precursors of lysosomal enzymes migrate from the rER to the cis-Golgi where mannose residues are phosphorylated.In the TGN,the phosphorylated enzymes bind to M6P receptors,which direct the enzymes into vesicles coated with the clathrin.The clathrin lattice surrounding these vesicles is
8、rapidly depolymerized to its subunits,and the uncoated transport vesicles fuse with late endosomes.Within this low-pH compartment,the phosphorylated enzymes dissociate from the M6P receptors and then are dephosphorylated.The receptors recycle back to the Golgi,and the enzymes are incorporated into a
9、 different transport vesicle that buds from the late endosome and soon fuses with a lysosome.The sorting of lysosomal enzymes from secretory proteins thus occurs in the TGN,and these two classes of proteins are incorporated into different vesicles,which take different routes after they bud from the
10、Golgi.G.Griffiths et al.,Cell 52:329;S.Kornfeld,Annu.Rev.Biochem.61:307;and G.Griffiths and J.Gruenberg,Trends Cell Biol.1:55.Protein Sorting Overview of sorting of nuclear-encoded proteins in eukaryotic cellsvProteins are imported into organelles by three mechanisms:Gated Transport:Transport throug
11、h nuclear poresTransmembrane transport:ER,Mit,Chl,PerVesicular transport:ER-Golgi-PM-Lys,EndosomevProtein sorting:Protein molecules move from the cytosol to their target organelles or cell surface directed by the sorting signals in the proteins.Signal peptides and Signal patchesFigure 6-8 Two ways t
12、hat a sorting signal can be built into a protein.(A)The signal resides in a single discrete stretch of amino acid sequence,called a signal peptide,that is exposed in the folded protein.Signal peptides often occur at the end of the polypeptide chain,but they can also be located elsewhere.(B)A signal
13、patch can be formed by the juxtaposition of amino acids from regions that are physically separated before the protein folds;alternatively,separate patches on the surface of the folded protein that are spaced a fixed distance apart could form the signal.Gated transport:Through gated poresNuclear pore
14、s;Nuclear localization signal(NLS);Folded and assembly form to transport.Transmembrane transportER signal sequence,Mit,Chl,Per:Leader sequence;Through translocon on the membrane;Single and Unfold form;Helped by molecular chaperonsVesicular transportBudding,transporting,docking and at last fusion with target membrane;Assembly coated proteins on the vesicles(Clathrin,COPII and COPI);Only Properly folded and assembled proteins;The orientation of transported proteins and lipids is not changed during transporting.
